The majority of HIV-1 isolates utilize either CXC chemokine receptor (CXCR) 4 and/or CC chemokine receptor (CCR)5 as primary entry coreceptors; alternative chemokine receptors are utilized less efficiently. The present study demonstrates cell surface expression of both CXCR4 and CCR5, the major coreceptors for T cell (T)-tropic and macrophage (M)-tropic strains of HIV, on CD34+ progenitor cells derived from the peripheral blood. CD34+ progenitor cells were susceptible to infection by diverse strains of HIV and infection could be sustained for prolonged periods in vitro. HIV entry into CD34+ progenitor cells was modulated by soluble (s) CD4, HIV gp 120 V3 loop neutralizing monoclonal antibody (mAb), and the cognate ligands for the CXCR4 and CCR5 HIV coreceptors. This study suggests that a significant proportion of the circulating progenitor cell pool may serve as a reservoir for HIV that is capable of trafficking the virus to diverse anatomic compartments. Furthermore, the infection and ultimate destruction of these progenitor cells may explain, in part, the defective lymphopoiesis in certain HIV- infected individuals despite effective control of virus replication during highly active anti-retroviral therapy.